This invention relates to the design, development, composition and use of novel molecules able to modulate the activity of inorganic ion receptor.
Certain cells in the body respond not only to chemical signals, but also to ions such as extracellular calcium ions (Ca2+). Changes in the concentration of extracellular Ca2+ (referred to herein as xe2x80x9c[Ca2+]xe2x80x9d) alter the functional responses of these cells. One such specialized cell is the parathyroid cell which secretes parathyroid hormone (PTH). PTH is the principal endocrine factor regulating Ca2+ homeostasis in the blood and extracellular fluids.
PTH, by acting on bone and kidney cells, increases the level of Ca2+ in the blood. This increase in [Ca2+] then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between [Ca2+] and PTH secretion forms the essential mechanism maintaining bodily Ca2+ homeostasis.
Extracellular Ca2+ acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cell surface protein which detects changes in [Ca2+] has been confirmed. Brown et al., 366 Nature 574, 1993. In parathyroid cells, this protein acts as a receptor for extracellular Ca2+ (xe2x80x9cthe calcium receptorxe2x80x9d), and detects changes in [Ca2+] and to initiate a functional cellular response, PTH secretion.
Extracellular Ca2+ can exert effects on different cell functions, reviewed in Nemeth et al., 11 Cell Calcium 319, 1990. The role of extracellular Ca2+ in parafollicular (C cells) and parathyroid cells is discussed in Nemeth, 11 Cell Calcium 323, 1990. These cells have been shown to express similar Ca2+ receptor. Brown et al., 366 Nature 574, 1993; Mithal et al., 9 Suppl. 1 J. Bone and Mineral Res. s282, 1994; Rogers et al., 9 Suppl. 1 J. Bone and Mineral Res. s409, 1994; Garrett et al., 9 Suppl. 1 J. Bone and Mineral Res. s409, 1994. The role of extracellular Ca2+ on bone osteoclasts is discussed by Zaidi, 10 Bioscience Reports 493, 1990. in addition keratinocytes, juxtaglomerular cells, trophoblasts, pancreatic beta cells and fat/adipose cells all respond to increases in extracellular calcium which likely reflects activation of calcium receptors of these cells.
The ability of various compounds to mimic extracellular Ca2+ in vitro is discussed by Nemeth et al., (spermine and spermidine) in xe2x80x9cCalcium-Binding Proteins in Health and Diseasexe2x80x9d, 1987, Academic Press, Inc., pp. 33-35; Brown et al., (e.g., neomycin) 128 Endocrinology 3047, 1991; Chen et al., (diltiazem and its analog, TA-3090) 5 J. Bone and Mineral Res. 581, 1990; and Zaidi et al., (verapamil) 167 Biochem. Biophys. Res. Commun. 807, 1990. Nemeth et al., PCT/US93/01642, International Publication Number WO 94/18959, Nemeth et al., PCT/US92/07175, International Publication Number WO 93/04373, Nemeth et al., PCT/US94/12117, International Publication Number WO 95/11221 and Nemeth et al., PCT/US95/13704, International Publication Number WO 96/12697 describe various compounds which can modulate the effect of an inorganic ion on a cell having an inorganic ion receptor, preferably modulate the effects of calcium on a calcium receptor.
The object of the present invention is to provide a novel inorganic ion receptor active compound having the structure different from the compounds described above.
The present invention features molecules which can modulate one or more activities of an inorganic ion receptor. Preferably, the molecule can mimic or block the effect of extracellular Ca2+ on a calcium receptor. The preferred use of such molecules is to treat diseases or disorders by altering inorganic ion receptor activity, preferably calcium receptor activity.
The present invention provides a novel calcium receptor active compound of the formula:
Ar1xe2x80x94[CR1R2]Pxe2x80x94Xxe2x80x94[CR3R4]qxe2x80x94[CR5R6]xe2x80x94NR7xe2x80x94[CR8R9]xe2x80x94Ar2xe2x80x83xe2x80x83(1)
wherein:
Ar1 is selected from the group consisting of aryl, heteroaryl, bis(arylmethyl)amino, bis(heteroarylmethyl)amino and arylmethyl(heteroarylmethyl)amino;
X is selected from the group consisting of oxygen, sulfur, sulfinyl, sulfonyl, carbonyl and amino;
R1, R2, R3, R4, R5, R6, R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, trihalomethyl, aryl, heteroaryl, heteroalicyclic, halogen, hydroxy, alkoxy, thioalkoxy, aryloxy, thioaryloxy, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, C-amido, N-amido, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, cyano, nitro, amino and NR10R11; wherein,
R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, carbonyl, trihaloacetyl, sulfonyl, trihalomethanesulfonyl and, combined, a five- or six-member heteroalicyclic ring containing at least one nitrogen;
any two adjacent xe2x80x9cRxe2x80x9d groups may be combined to form five- or six-member fused cycloalkyl groups;
R7 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, halogen, cyano, hydroxy, alkoxy, O-carboxyl, trihaloacetyl and trihalomethanesulfonyl;
Ar2 is selected from the group consisting of aryl and heteroaryl;
p is an integer of from 0 to 6, inclusive; and,
q is an integer of from 0 to 14, inclusive;
or a pharmaceutically acceptable salt or hydrate of said compound.
As used herein, the term xe2x80x9carylxe2x80x9d refers to an all-carbon monocyclic or fused ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups in which one or more of the rings has a completely conjugated pi-electron system. Examples, without limitation, of aryl groups, are phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, and indanyl. The aryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from halogen, trihalomethyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, sulfonyl, S-sulfonamido, N-sulfonamido, trihalomethane-sulfonamido, amino and NR10R11 wherein:
R10 and R11 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, carbonyl, sulfonyl, trihalomethanesulfonyl, and, combined, a five- or six-member heteroalicyclic ring which heteroalicyclic ring may be unsubstituted or substituted with one or more halogens.
A xe2x80x9cheteroarylxe2x80x9d group refers to a monocyclic or fused ring (i.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur and, in addition, at least one of the rings has a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups are pyrrole, furan, dibenzofuran, carbazole, acridine, thiophene, imidazole, benzimidazole, oxazole, thiazole, phenothiazine, triazole, thiadiazole, pyrazole, benzoxazole, benzthiazole, indole, benzofuran, indazole, pyridine, pyrimidine, quinoline, isoquinoline, quinazoline, purine, phthalazine and flavone. The heteroaryl group may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, halogen, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, sulfonamido, C-carboxy, O-carboxy, sulfinyl, sulfonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, trihalomethanesulfonamido, amino and NR10R11 where R10 and R11 are previously defined herein.
As used herein, the term xe2x80x9calkylxe2x80x9d refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, it is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, sulfonamido, trihalomethane-sulfonamido, amino and NR10R11 where R10 and R11 are previously defined herein. More preferably, the alkyl group is a medium or lower alkyl which is optionally substituted with one or more groups independently selected from halogen, hydroxy, nitro, cyano and unsubstituted lower alkoxy, lower alkoxy substituted with one or more halogens; an unsubstituted lower alkyl; and a lower alkyl substituted with one or more halogens.
A xe2x80x9ccycloalkylxe2x80x9d group refers to an all-carbon monocyclic or fused ring (i.e., rings which share an adjacent pair of carbon atoms) group wherein none of the rings has a completely conjugated pi-electron system. Examples, without limitation, of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, cycloheptane and, cycloheptatriene. A cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more individually selected from alkyl, aryl, heteroaryl, heteroalycyclic, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, halogen, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, nitro, amino and NR10R11, where R10 and R11 are previously defined herein. Preferably the cycloalkyl group is selected from unsubstituted cyclopropane, unsubstituted cyclopentane, unsubstituted cyclohexane, and cyclopropane, cyclopentane and cyclohexane substituted with one or more groups independently selected from halogen, nitro, cyano, hydroxy, unsubstituted lower alkoxy, C-carboxyl wherein Rxe2x80x3 is unsubstituted lower alkyl and O-carboxyl wherein Rxe2x80x3 is unsubstituted lower alkyl.
An xe2x80x9calkenylxe2x80x9d group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon double bond. A xe2x80x9clower alkenylxe2x80x9d group refers to a lower alkyl group containing at least one double bond.
A xe2x80x9ccycloalkenylxe2x80x9d group refers to a cycloalkyl group which contains one or more double bonds in the ring wherein the double bonds do not produce a completely conjugated pi-electron system within the ring.
An xe2x80x9calkynylxe2x80x9d group refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. A xe2x80x9clower alkynylxe2x80x9d group refers to a lower alkyl group containing at least one triple bond.
A xe2x80x9cheteroalicyclicxe2x80x9d group refers to a monocyclic or fused ring group having in the ring(s) one or more atoms selected from the group consisting of nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, none of the rings has a completely conjugated pi-electron system. The heteroalicyclic ring may be substituted or unsubstituted. When substituted, the substituted group(s) is preferably one or more selected from alkyl, cycloalkyl, halogen, trihalomethyl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, sulfinyl, sulfonyl, S-sulfonamido, N-sulfonamido, C-amido, N-amido, amino and NR10R11 where R10 and R11 are previously defined herein.
A xe2x80x9cphenylxe2x80x9d group refers to a six-member ring aryl group.
A xe2x80x9cbenzylxe2x80x9d group refers to a phenyl-CH2-group.
A xe2x80x9chydroxyxe2x80x9d group refers to an xe2x80x94OH group.
An xe2x80x9calkoxyxe2x80x9d group refers to both an xe2x80x94O-alkyl and an xe2x80x94O-cycloalkyl group, as defined herein; preferably an alkoxy group refers to a methoxy or trihalomethoxy.
A xe2x80x9ctrihalomethoxyxe2x80x9d group refers to a Y3CO-group with Y as defined herein; preferably Y is fluorine.
A xe2x80x9cbenzyloxyxe2x80x9d refers to a benzyl-O-group.
An xe2x80x9caryloxyxe2x80x9d group refers to both an xe2x80x94O-aryl and an xe2x80x94O-heteroaryl group, as defined herein. A xe2x80x9cphenoxyxe2x80x9d group refers to an aryloxy group in which the aryl group is a phenyl group. A xe2x80x9cthiohydroxyxe2x80x9d group refers to an xe2x80x94SH group.
A xe2x80x9cthioalkoxyxe2x80x9d group refers to both an S-alkyl and an xe2x80x94S-cycloalkyl group, as defined herein.
A xe2x80x9cthioaryloxyxe2x80x9d group refers to both an xe2x80x94S-aryl and an xe2x80x94S-heteroaryl group, as defined herein.
A xe2x80x9ccarbonylxe2x80x9d or xe2x80x9cacylxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)xe2x80x94Rxe2x80x3 group, where Rxe2x80x3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), as defined herein.
An xe2x80x9cformylxe2x80x9d group refers to a carbonyl group wherein Rxe2x80x3 is hydrogen.
An xe2x80x9cacetylxe2x80x9d group refers to a carbonyl group wherein Rxe2x80x3 is CH3.
A xe2x80x9cthiocarbonylxe2x80x9d group refers to a xe2x80x94C(xe2x95x90S)xe2x80x94Rxe2x80x3 group, with Rxe2x80x3 as defined herein.
A xe2x80x9ctrihalomethylxe2x80x9d group refers to a xe2x80x94CY3 group wherein Y is a halogen group; preferably Y is fluorine.
A xe2x80x9ctrihaloacetylxe2x80x9d group refers to a Y3CC(xe2x95x90O)-group with Y as defined herein.
A xe2x80x9cC-carboxylxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)Oxe2x80x94Rxe2x80x3 groups, with Rxe2x80x3 as defined herein.
An xe2x80x9cO-carboxylxe2x80x9d group refers to a Rxe2x80x3C(xe2x95x90O)O-group, with Rxe2x80x3 as defined herein.
An xe2x80x9cacetoxyxe2x80x9d group refers to an O-carboxyl group in which Rxe2x80x3 is CH3.
A xe2x80x9ccarboxylic acidxe2x80x9d group refers to a C-carboxyl group in which Rxe2x80x3 is hydrogen.
A xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d group refers to fluorine, chlorine, bromine or iodine.
A xe2x80x9ctrihalomethanesulfonylxe2x80x9d group refers to a Y3CS(xe2x95x90O)2-groups with Y as defined above.
A xe2x80x9ctrihalomethanesulfonamidoxe2x80x9d group refers to a Y3CS(xe2x95x90O)2NR10-group with Y and R10 as defined herein.
A xe2x80x9csulfinylxe2x80x9d group refers to a xe2x80x94S(xe2x95x90O)xe2x80x94Rxe2x80x3 group, with Rxe2x80x3 as defined herein or Rxe2x80x3 may not exist if both S-bonds are already in use internally in a particular molecule.
A xe2x80x9csulfonylxe2x80x9d group refers to a xe2x80x94S(xe2x95x90O)2Rxe2x80x3 group, with Rxe2x80x3 as defined herein or Rxe2x80x3 may not exist is both S-bonds are already in use internally in an particular molecule.
An xe2x80x9cS-sulfonamidoxe2x80x9d group refers to a xe2x80x94S(xe2x95x90O)2NR10R11, with R10 and R11 as defined herein.
An xe2x80x9cN-sulfonamidoxe2x80x9d group refers to a R10S(xe2x95x90O)2NR11-group, with R10 and R11 as defined herein.
An xe2x80x9cO-carbamylxe2x80x9d group refers to a xe2x80x94OC(xe2x95x90O)NR10R11 group with R10 and R11 as defined herein.
An xe2x80x9cN-carbamylxe2x80x9d group refers to a R10OC(xe2x95x90O)NR11-group, with R10 and R11 as defined herein.
An xe2x80x9cO-thiocarbamylxe2x80x9d group refers to a xe2x80x94OC(xe2x95x90S)NR10R11 group with R10 and R11 as defined herein.
An xe2x80x9cN-thiocarbamylxe2x80x9d group refers to a R10OC(xe2x95x90S)NR11-group, with R10 and R11 as defined herein.
An xe2x80x9caminoxe2x80x9d group refers to an xe2x80x94NR10R11 group, with R10 and R11 as defined herein.
A xe2x80x9cC-amidoxe2x80x9d group refers to a xe2x80x94C(xe2x95x90O)NR10R11 group with R10 and R11 as defined herein.
An xe2x80x9cN-amidoxe2x80x9d group refers to a R10C(xe2x95x90O)NR11-group, with R10 and R11 as defined herein.
A xe2x80x9cnitroxe2x80x9d group refers to a xe2x80x94NO2 group.
A xe2x80x9cmethylenedioxyxe2x80x9d group refers to a xe2x80x94OCH2O-group in which the two oxygens are covalently bonded to adjacent carbon atoms of an aryl or heteroaryl group.
An xe2x80x9cethylenedioxyxe2x80x9d group refers to a xe2x80x94OCH2CH2O-groups in which the two oxygens are covalently bonded to adjacent carbon atoms of an aryl or heteroaryl group.
Preferably, in the formula (1), R5 is selected from the group consisting of hydrogen, unsubstituted lower alkyl and lower alkyl substituted with one or more halogens; R1, R2, R3, R4, R5, R6 and R7 are hydrogen; and R8 and R9 are independently selected from the group consisting of hydrogen, unsubstituted alkyl, lower alkyl substituted with one or more halogens, unsubstituted alkenyl, lower alkenyl substituted with one or more halogens, unsubstituted alkynyl, alkynyl substituted with one or more halogens and, combined, unsubstituted cycloalkyl and cycloalkenyl. Also preferably, Ar1 is selected from the group consisting of phenyl, naphthyl, indolyl, fluorenyl, dibenzofuranyl, carbazolyl, benzoxazole-2-yl, benzthiazole-2-yl, pyridin-4-yl, quinolin-2-yl and dibenzylamino and Ar2 is selected from the group consisting of phenyl, naphthyl, quinolin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidinyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, pyrrol-2-yl and pyrrol-3-yl. More preferably, Ar1 is phenyl substituted with one or more groups selected from the group consisting of unsubstituted lower alkyl, halogen, trihalomethyl, unsubstituted lower alkoxy, trihalomethoxy, trihaloacetyl and nitro, and Ar2 is selected from the group consisting of optionally substituted phenyl and optionally substituted naphthyl. Even more preferably, Ar2 is 3-methoxyphenyl or unsubstituted naphthyl. Preferably, R8 is hydrogen, R9 is methyl and X is oxygen or sulfur.
In another aspect, the present invention provides a compound of the formula:
Ar3xe2x80x94(CHR12)rxe2x80x94Qxe2x80x94(CH2)sxe2x80x94CHR13xe2x80x94NHxe2x80x94CR14R15xe2x80x94Ar4xe2x80x83xe2x80x83(2)
wherein:
Ar3 is selected from the group consisting of aryl and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halogens, unsubstituted lower alkenyl, lower alkenyl substituted with one or more halogens, halogen, hydroxy, unsubstituted lower alkoxy, lower alkoxy substituted with one or more halogens, unsubstituted lower thioalkoxy, nitro, formyl, acetoxy, acetyl, xe2x80x94CH2OH, CH3CH(OH)xe2x80x94, xe2x80x94C(xe2x95x90O)NH2, cyano, xe2x80x94N(lower alkyl)2, phenyl, phenoxy, benzyl, benzyloxy, methylenedioxy, ethylenedioxy, xcex1, xcex1-dimethylbenzyl, and xe2x80x94OCH2COOH;
Ar4 is selected from the group consisting of aryl and heteroaryl optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halogens, unsubstituted lower alkenyl, lower alkenyl substituted with one or more halogens, unsubstituted lower alkoxy, lower alkoxy substituted with one or more halogens, hydroxy, lower thioalkoxy, halogen, methylenedioxy, ethylenedioxy, acetoxy, xe2x80x94OCH2COOH, xe2x80x94C(xe2x95x90O)NH2, cyano, and xe2x80x94CH2OH;
r is an integer of from 0 to 6, inclusive;
S is an integer of from 0 to 14, inclusive;
Q is selected from the group consisting of oxygen, sulfur, carbonyl and -NH-;
R13 is hydrogen or lower alkyl; and
R14 and R15 are independently selected from the group consisting of hydrogen, alkyl and, combined, cycloalkyl and cycloalkenyl;
or a pharmaceutically acceptable salt or hydrate of said compound.
Preferably, in the formula (2), Ar3 is selected from the groups consisting of unsubstituted phenyl, phenyl substituted with one or more groups selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halogens, halogen, unsubstituted lower alkoxy, lower alkoxy substituted with one or more halogens, nitro, dimethylamino and unsubstituted phenyl, and optionally substituted naphthyl; and Ar4 is selected from the groups consisting of unsubstituted phenyl, phenyl substituted with one or more groups selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halogens, unsubstituted lower alkoxy, lower alkoxy substituted with one or more halogens, and halogen, and optionally substituted naphthyl.
In another aspect, the present invention provides a compound of the formula:
Ar5xe2x80x94(CHR16)txe2x80x94Wxe2x80x94(CH2)uxe2x80x94CHR17xe2x80x94NHxe2x80x94CH(R18)xe2x80x94Ar6xe2x80x83xe2x80x83(3)
wherein:
Ar5 is aryl, dicyclic or tricyclic heteroaryl, arylmethyl(arylmethyl)amino, heteroarylmethy(heteroarylmethyl)amino or arylmethyl(heteroarylmethyl)amino optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, unsubstituted lower alkenyl, halogen, hydroxy, unsubstituted lower alkoxy, unsubstituted lower thioalkoxy, lower alkyl substituted with one or more halogens, lower alkenyl substituted with one or more halogens, lower alkoxy substituted with one or more halogens, nitro, formyl, acetoxy, acetyl, xe2x80x94CH2OH, CH3CH(OH)xe2x80x94, xe2x80x94C(xe2x95x90O)NH2, cyano, xe2x80x94N(unsubstituted lower alkyl)2, phenyl, phenoxy, benzyl, benzyloxy, xcex1, xcex1-dimethylbenzyl, methylenedioxy, ethylenedioxy and xe2x80x94OCH2COOH;
Ar6 is aryl or dicyclic or tricyclic heteroaryl optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, lower alkyl substituted with one or more halogens, unsubstituted lower alkenyl, lower alkenyl substituted with one or more halogens, unsubstituted lower alkoxy, lower alkoxy substituted with one or more halogens, halogen, hydroxy, unsubstituted lower thioalkoxy, lower thioalkoxy substituted with one or more halogens, benzyloxy, methylenedioxy, ethylenedioxy, acetoxy, xe2x80x94OCH2COOH, xe2x80x94C(xe2x95x90O)NH2, cyano, and xe2x80x94CH2OH;
t is 0 or 1;
u is an integer of from 0 to 11, inclusive;
W is selected from the group consisting of oxygen, sulfur, sulfinyl, sulfonyl, carbonyl and amino;
R16 and R17 are H or unsubstituted lower alkyl; and
R18 is unsubstituted lower alkyl;
or a pharmaceutically acceptable salt or hydrate of said compound.
Preferably, in the formula (3), Ar5 is phenyl, indole, benzothiazole, benzoxazole, dibenzofuran, carbazole, pyridine, fluorene, quinoline, naphthalene, chromenone, tetrahydrobenzothiazepine, dibenzylamino, benzyl(naphthylmethyl)amino, benzyl(pyridylmethyl)amino, thienylmethyl(benzyl)amino, furylmethyl(benzyl)amino or N-alkyl-pyrrolylmethyl(benzyl)amino optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, halogen, unsubstituted lower alkoxy, lower alkyl substituted with one or more halogens, lower alkoxy substituted with one or more halogens, nitro, dimethylamino and unsubstituted phenyl; and Ar6 is thiophene, furan, pyrrole, phenyl, naphthalene, pyridine, pyrazine or thiazole optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, halogen, unsubstituted lower alkoxy, lower alkyl substituted with one or more halogens, lower alkoxy substituted with one or more halogens, hydroxy and benzyloxy optionally substituted with halogen or methyl. More preferably, Ar5 is selected from the group consisting of phenyl optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, halogen, unsubstituted lower alkoxy, lower alkyl substituted with one or more halogens and lower alkoxy substituted with one or more halogens; and Ar6 is 3-methoxyphenyl or xcex1-naphthyl, more preferably, xcex1-naphthyl. Also preferably, Ar5 is dibenzylamino, benzyl(naphthylmethyl)amino or benzyl(pyridylmethyl)amino optionally substituted with one or more groups independently selected from the group consisting of unsubstituted lower alkyl, halogen, unsubstituted lower alkoxy, lower alkyl substituted with one or more halogens and lower alkoxy substituted with one or more halogens, and Ar6 is naphthyl or methoxyphenyl. More preferably, Ar5 is dibenzylamino optionally substituted with unsubstituted alkyl, and Ar6 is xcex1-naphthyl.
Preferably, the compound of the present invention represented by the formulae (1), (2) or (3) is the R enantiomer. The present invention also provides a prodrug of any of the compounds described above.
The present invention provides a method for modulating calcium receptor activity by using a compound described herein. The featured compounds preferably modulate an interaction of Ca2+ with Ca2+ receptors by mimicking (including potentiating) the effect of Ca2+ on a Ca2+ receptor (calcimimetic modulation) or blocking the effect of Ca2+ on a Ca2+ receptor (calcilytic modulation); preferably calcimimetic modulation.
Also provided is a method for the treatment in a patient of disorders characterized by an abnormal concentrations of one or more inorganic ions or other physiological biochemical substances, the concentration of which is regulated by an activity of one or more calcium receptors. In particular, treatment using the compounds disclosed hereof is contemplated for disorders characterized by abnormal extracellular Ca2+ concentration ([Ca2+]) or abnormal intracellular Ca2+ concentration ([Ca2+]i) in one or more cells including for example, but without limitation, parathyroid cells, bone osteoclasts, juxtaglomerular kidney cells, proximal tubule kidney cells, keratinocytes, parafollicular thyroid cells and placental trophoblasts.
An xe2x80x9cabnormalxe2x80x9d state is characterized by a level of a property that is statistically different from the level of that property observed in patients not suffering from a particular disorder. Thus, for example, the term xe2x80x9cabnormalxe2x80x9d as it relates to inorganic ion concentrations refers to a concentration of the ion in question which would be recognized by members of the medical community as being outside the normal range of such ion concentration in healthy patients.
As used herein, the terms xe2x80x9ctreatxe2x80x9d, xe2x80x9ctreatingxe2x80x9d and xe2x80x9ctreatmentxe2x80x9d refer to a method of alleviating, abrogating, and/or having a prophylactic effect with regard to, a disease or disorder and/or one or more, preferably all, its attendant symptoms.
In another aspect, the present invention provides a method for the treatment or prevention of primary and secondary hyperparathyroidism, renalosteodystrophy, hypercalcemia malignancy, osteoporosis, Paget""s disease and hypertension comprising administering a therapeutically effective amount of a compound of this invention to a patient.
The term xe2x80x9cadministeringxe2x80x9d as used herein refers to a method for introducing a compound of this invention in vitro or in vivo. Thus, for example, the importance of inorganic ion receptor activity can be studied and associated diseases and disorders prevented or treated by the compounds and methods set forth herein. Cells existing outside the organism can be maintained or grown in cell culture dishes. In this context, the ability of a particular compound to affect an inorganic ion receptor activity can be determined; i.e., the IC50 or EC50, preferably the EC50, of a compound, defined below, before the use of the compounds in complex multicellular living organisms such as a human is attempted. For cells outside the organism, multiple methods exist, and are well-known to those skilled in the arts, to administer compounds including, but not limited to, cell micro-injection, transformation and numerous carrier techniques.
For cells harbored within a multicellular living organism, myriad methods also exist, and are likewise well-known to those skilled in the art, to administer compounds including, but not limited to, oral, parenteral, dermal, injection and aerosol applications.
The present invention features a method for the modulation of one or more activities of an inorganic ion receptor using the compounds disclosed herein. Preferably, the inorganic ion receptor is a Ca2+ receptor. The compounds of this invention can either mimic (including potentiation) or block the effect of extracellular Ca2+ on a calcium receptor. The preferred use of such compounds is to treat selected disorders by modulating the inorganic ion receptor activity. In particular the compounds of this invention can be used to treat the indicated disorders by modulating Ca2+ receptor activity.
Extracellular Ca2+ is under tight homeostatic control and controls various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca2+ concentration. For example, extracellular Ca2+ inhibits the secretion of parathyroid hormone from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells.
Compounds modulating inorganic ion receptor activity can be used to treat diseases or disorders by affecting one or more activities of an inorganic ion receptor resulting in a beneficial effect to the patient. For example, osteoporosis is an age related disorder characterized by loss of bone mass and increased risk of bone fracture. Compounds blocking osteoclastic bone resorption either directly (e.g., a osteoclast ionmimetic compound) or indirectly by increasing endogenous calcitonin levels (e.g., a C-cell ionmimetic), and/or by decreasing parathyroid hormone levels (e.g., a parathyroid cell ionmimetic) can retard bone loss and, thus, result in beneficial effects to patients suffering from osteoporosis.
In addition, it is known that intermittent low dosing with PTH results in an anabolic effect on bone mass and appropriate bone remodeling. Thus, compounds and dosing regiments evoking transient increases in parathyroid hormone (e.g., intermittent dosing with a parathyroid cell ionlytic) can increase bone mass in patients suffering from osteoporosis.
Additionally, diseases or disorders characterized by a defect in one or more inorganic ion receptor activities may be treated by the present invention. For example, certain forms of primary hyperparathyroidism are characterized by abnormally high levels of parathyroid hormone and decreased parathyroid gland responsiveness to circulating calcium. Calcium receptor modulating agents can be used to modulate parathyroid cell responsiveness to calcium.
Preferably, the compound modulates calcium receptor activity and is used in the treatment of diseases or disorders which can be affected by modulating one or more activities of a calcium receptor. Preferably, the disease or disorder is characterized by abnormal bone and mineral homeostasis, more preferably calcium homeostasis.
Abnormal calcium homeostasis is characterized by one or more of the following activities: (1) an abnormal increase or decrease in serum calcium; (2) an abnormal increase or decrease in urinary excretion of calcium; (3) an abnormal increase or decrease in bone calcium levels, for example, as assessed by bone mineral density measurements; (4) an abnormal absorption of dietary calcium; and (5) an abnormal increase or decrease in the production and/or release of circulating messengers or hormones which affect calcium homeostasis such as parathyroid hormone and calcitonin. The abnormal increase or decrease in these different aspects of calcium homeostasis is relative to that occurring in the general population and is generally associated with a disease or disorder.
More generally, a molecule which modulates the activity of an inorganic ion receptor is useful in the treatment of diseases characterized by abnormal inorganic ion homeostasis. Preferably, the molecule modulates one or more effects of an inorganic ion receptor. Inorganic ion receptor modulating agents include ionmimetics, ionlytics, calcimimetics, and calcilytics.
Ionmimetics are molecules which mimic the effects of increasing ion concentration at an inorganic ion receptor. Preferably, the molecule affects one or more calcium receptor activities. Calcimimetics are ionmimetics which affect one or more calcium receptor activities and preferably binds to a calcium receptor.
Ionlytics are molecules which reduce or block one or more activities caused by an inorganic ion on an inorganic ion receptor. Preferably, the molecule inhibits one or more calcium receptor activities. Calcilytics are ionlytics which inhibit one or more calcium receptor activities evoked by extracellular calcium and preferably bind to a calcium receptor.
Inorganic ion receptor modulating agents can be formulated as pharmacological agents or compositions to facilitate administration in a patient. Pharmacological agents or compositions are agents or compositions in a form suitable for administration into a mammal, preferably a human. Considerations concerning forms suitable for administration are known in the art and include toxic effects, solubility, route of administration, and maintaining activity.
Other aspects of the present invention feature methods for using the agents described herein for treating diseases or disorders by modulating inorganic ion receptor activity. Patients in need of such treatments can be identified by standard medical techniques, such as routine blood analysis. For example, by detecting a deficiency of protein whose production or secretion is affected by changes in inorganic ion concentrations, or by detecting abnormal levels of inorganic ions or hormones which effect inorganic ion homeostasis.
Therapeutic methods involve administering to the patient a therapeutically effective amount of an inorganic ion receptor modulating agent. In preferred embodiments these methods are used to treat a disease or disorder characterized by abnormal inorganic ion homeostasis, more preferably a disease or disorder characterized by abnormal calcium homeostasis. Diseases and disorders characterized by abnormal calcium homeostasis include hyperparathyroidism, osteoporosis, renalosteodystrophy and other bone and mineral-related disorders, and the like (as described, e.g., in standard medical text books, such as xe2x80x9cHarrison""s Principles of Internal Medicinexe2x80x9d). Such diseases and disorders are treated using calcium receptor modulating agents which mimic or block one or more of the effects of Ca2+ and, thereby, directly or indirectly affect the levels of proteins or other molecules in the body of the patient.
By xe2x80x9ctherapeutically effective amountxe2x80x9d is meant an amount of an agent which relieves to some extent one or more symptoms of the disease or disorder in the patient; or returns to normal either partially or completely one or more physiological or biochemical parameters associated with or causative of the disease or disorder.
In a preferred embodiment, the patient has a disease or disorder characterized by an abnormal level of one or more calcium receptor regulated components and the molecule is active on a calcium receptor of a cell selected from the group consisting of parathyroid cell, bone osteoclast, juxtaglomerular kidney cell, proximal tubule kidney cell, distal tubule kidney cell, central nervous system cell, peripheral nervous system cell, cell of the thick ascending limb of Henle""s loop and/or collecting duct, keratinocyte in the epidermis, parafollicular cell in the thyroid (C-cell), intestinal cell, trophoblast in the placenta, platelet, vascular smooth muscle cell, cardiac atrial cell, gastrin-secreting cell, glucagon-secreting cell, kidney mesangial cell, mammary cell, beta cell, fat/adipose cell, immune cell and GI tract cell.
More preferably, the cell is a parathyroid cell and the molecule reduces the level of parathyroid hormone in the serum of the patient, even more preferably the level is reduced to a degree sufficient to cause a decrease in plasma Ca2+, most preferably the parathyroid hormone level is reduced to that present in a normal individual.
Thus, the present invention features agents and methods useful in the treatment of diseases and disorders by modulating inorganic ion receptor activity. For example, the molecules of the present invention can be used to target calcium receptors on different cell types that detect and respond to changes to external calcium. For example, molecules mimicking external calcium may be used to selectively depress secretion of parathyroid hormone from parathyroid cells, or depress bone resorption by osteoclasts, or stimulate secretion of calcitonin from C-cells. Such molecules can be used to treat diseases or disorders characterized by abnormal calcium homeostasis such as hyperparathyroidism, renalosteodystrophy and osteoporosis.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof and from the claims.